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Key value for chemical safety assessment

Effects on fertility

Description of key information

One repeated dose toxicity study according to OECD guideline 422 was conducted to obtain information on possible effects of the test item DiPT on general toxicity, reproduction and/or development .

No influence was noted on the fertility and the reproductive parameters of the parental generation (F0-Generation) with respect to fertility, pre-coital time, gestation length, gestation index, number of stillbirths, birth and live birth index and the preand post-implantation loss for any of the examined dose levels.

The NOAEL for adverse effects on fertility and reproduction parameters is above the highest administered dose 1000 mg test item/kg b.w./day, p.o..

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
other: CD/Crl:CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
Sandhofer Weg 7
97633 Sulzfeld
Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Males (MS, RC)+ Females (MS, RC): 71 days
- Weight at study initiation:
Males (MS): 345.9 - 390.5 g
Males (RC): 350.6 - 372.8 g
Females (MS): 219.7 - 261.1 g
Females (RC): 229.5 - 255.9 g
- Housing:
With the exception of the mating period (see Section 3.9 'Mating procedure'), the
males and females (F0-Generation) were kept singly in MAKROLON cages (type III
plus) with a basal surface of approx. 39 cm x 23 cm and a height of approx.
18 cm.
- Diet : ad libitum
- Water: ad libitum
- Acclimation period: 6 days

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C
- Humidity (%): 55% ± 15%
- Photoperiod (hrs dark / hrs light): The rooms were alternately lit (about 150 lux at approx. 1.5 m room height) and
darkened for periods of 12 hours.

IN-LIFE DATES:
First administration March 18, 2015
End of the in-life period Males: MS: April 16, 2015
RC: May 12, 2015
Females: MS: May 02, 2015
RC: May 12, 2015
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:

VEHICLE
- Amount of vehicle (if gavage): 2 mL/kg b.w./day
Details on mating procedure:
- M/F ratio per cage: 1 male and 1 female animal were placed in one cage during the dark period.
- Length of cohabitation: until pregnancy had occured
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- After successful mating each pregnant female was caged (how): single
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Method: HPLC-UV Detection
Duration of treatment / exposure:
Main study: The male rats were dosed from test day one until, and including, test day 29 and were sacrificed on test day 30. The female rats were dosed between test day one and test day 40 (first sacrificed female on test day 41) or test day 45 (last sacrificed female on test day 46).
Recovery: The maöes and females were dosed from test day one until, and including, test day 40 and were sacrificed on test day 56.
Frequency of treatment:
Once daily
Remarks:
Doses / Concentrations:
Group 2: 100 mg/kg b.w./day
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
Group 3: 300 mg/kg b.w./day
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
Group 4: 1000 mg/kg b.w./day
Basis:
analytical conc.
No. of animals per sex per dose:
Main study: 12 animals/sex/dose
Recovery: 5 animals/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected by the Sponsor based on available toxicological data and a 14-day dose range finding study
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at leat once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily; individual animals were observed before and after dosing at each time of dosing

BODY WEIGHT: Yes
- Time schedule for examinations:Males and females were weighed on the first day of dosing, weekly thereafter and at termination. During gestation, females were weighed on days 0, 7, 14 and 20 and within 24 hours of parturition (day 1 post-partum) and day 4 post-partum.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for individual animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: daily by visual appraisal

Sperm parameters (parental animals):
Parameters examined in [group 1 and 4] male parental generations:
Detailed histopathological examination was performed on one testicle and one epididymis with special emphasis of the qualitative stages of spermatogenesis and histopathology of interstitial testicular structure of the selected male animals of the main study groups 1 and 4.
Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes
Postmortem examinations (parental animals):
SACRIFICE
- Main study Male animals: All surviving animals were sacrified on test day 30.
- Main study Maternal animals: All surviving animals were sacrified 24 days after the last day of the mating period.
-Recovery study:All male and female animals allocated to the recovery period were sacrificed on test day 56.

GROSS NECROPSY
All superficial tissues were examined visually and by palpation and the cranial roof removed to allow observation of the brain, pituitary gland and cranial nerves. After ventral midline incision and skin reflection all subcutaneous tissues were examined. The condition of the thoracic viscera was noted with due attention to the thymus, lymph nodes and heart. The abdominal viscera were examined before and after removal. The urinary bladder was examined externally and by palpation. The gastro-intestinal tract was examined as a whole and the stomach and caecum were incised and examined. The lungs were removed and all pleural surfaces were examined under suitable illumination. The liver and the kidneys were examined. Any abnormalities in the appearance and size of the
gonads, adrenals, uterus.

HISTOPATHOLOGY / ORGAN WEIGHTS

The following tissues were prepared for microscopic examination:
Epididymis (2)
Gross lesions
Mammary gland (females only)
Ovary (2)
Prostate
Seminal vesicle
Testicle (2)
Uterus (incl. cervix and oviducts)
Vagina
Adrenal gland (2)
Bone marrow (os femoris)
Brain (cerebrum, cerebellum, brain stem)
Heart (left and right ventricle, septum)
Intestine, small (duodenum, jejunum, ileum,
incl. Peyer's patches, Swiss roll method)
Intestine, large (colon, rectum)
Kidney and ureter (2)
Liver
Lungs (with mainstem bronchi and
bronchioles), preserved by inflation with
fixative and then immersion
Lymph node (1, cervical)
Lymph node (1, mesenteric)
Nerve (sciatic)
Spinal cord (3 sections)
Spleen
Stomach
Thyroid (incl. parathyroid)
Thymus
Tissue masses or tumours (incl.
regional lymph nodes)
Trachea (incl. larynx)
Urinary bladder

The weights of the following organs were determined:
Adrenal gland (2)
Brain
Heart
Kidney (2)
Liver
Spleen
Thymus
Postmortem examinations (offspring):

GROSS NECROPSY
Dead pups and pups sacrificed at day 4 post-partum were carefully examined externally
for gross abnormalities.
Statistics:
Statistical analyses of the parametrical values, captured or calculated by Provantis (i.e. clinical signs, parental body weight, body weight gain,
food consumption,haematological and biochemical parameters), were done by Provantis.
Reproductive indices:
The following indices were calculated for each group:
Male fertility Index [%]
Female fertility Index [%]
Gestation Index [%]
Birth Index [%]
Live Birth Index [%]
Survival Index [%]
Pre-implantation loss [%]
Post-implantation loss [%]
Clinical signs:
effects observed, non-treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Food efficiency:
effects observed, non-treatment-related
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Clinical biochemistry findings:
effects observed, non-treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related influence was noted on the
mean number of corpora lutea per dam, the mean
number of implantation sites per dam, the mean
number of pups born (alive and dead) per dam,
the mean number live born pups per dam and the
reproductive indices (birth index, live birth index,
pre- and post implantation loss).
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects for systemic toxicity and on fertility and reproductive parameters were recorded until the highest dose of 1000 mg/kg bw.
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
Clinical signs:
not examined
Mortality / viability:
mortality observed, non-treatment-related
Body weight and weight changes:
effects observed, non-treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Histopathological findings:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects on the development of the pups were recorded.
Key result
Reproductive effects observed:
no
Conclusions:
The aim of the study was to obtain information on possible effects of the test item
on general toxicity, reproduction and/or development according to OECD guideline
422. The test item Di-(iso)-pentyl terephthalate (DPT) was administered orally to
rats at dose levels of 100, 300 or 1000 mg test item/kg b.w./day.

General toxicity
No premature death, no test item-related signs of clinical toxicity and no test itemrelated
influence on the neurological function were noted for animals of the main
and the recovery study.
Body weight, food consumption and the haematological and biochemical parameters
were not influenced by the test item.
Necropsy revealed no test item related changes during the macroscopic and microscopic
examinations and on the weights of the examined organs.

Reproductive toxicity
No influence was noted on the fertility and the reproductive parameters of the parental
generation (F0-Generation) with respect to fertility, pre-coital time, gestation
length, gestation index, number of stillbirths, birth and live birth index and the preand
post-implantation loss for any of the examined dose levels.
No adverse effects were noted on the development of the pups (F1-Generation)
with respect to survival index, body weight, and gross abnormalities.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 200 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

One repeated dose toxicity study according to OECD guideline 422 was conducted to obtain information on possible effects of the test item DiPT on general toxicity, reproduction and/or development .

No adverse effects were noted on the development of the pups (F1-Generation) with respect to survival index, body weight, and gross abnormalities. The NOAEL for adverse effects on the development of the pups

is above the highest administered dose 1000 mg test item/kg b.w./day, p.o..

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
10 000 mg/m³
Study duration:
subacute
Species:
other: rat and rabbit
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

No classification for reproductive toxicity is indicated according to the classification, labeling, and packaging (CLP) regulation (EC) No 1272/2008.

Additional information